Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis

Artur V Cideciyan; Tomas S Aleman; Samuel G Jacobson; Hemant Khanna; Alexander Sumaroka; Geoffrey K Aguirre; Sharon B Schwartz; Elizabeth A M Windsor; Shirley He; Bo Chang; Edwin M Stone; Anand Swaroop

doi:10.1002/humu.20565

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Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis

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Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis

Artur V Cideciyan, Tomas S Aleman, Samuel G Jacobson, Hemant Khanna, Alexander Sumaroka, Geoffrey K Aguirre, Sharon B Schwartz, Elizabeth A M Windsor, Shirley He, Bo Chang, …

Human mutation, Vol.28(11), pp.1074-1083

11/2007

DOI: 10.1002/humu.20565

PMID: 17554762

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https://hdl.handle.net/2027.42/57387View

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Abstract

Mutations in the centrosomal-ciliary gene CEP290/NPHP6 are associated with Joubert syndrome and are the most common cause of the childhood recessive blindness known as Leber congenital amaurosis (LCA). An in-frame deletion in Cep290 shows rapid degeneration in the rod-rich mouse retina. To explore the mechanisms of the human retinal disease, we studied CEP290-LCA in patients of different ages (7-48 years) and compared results to Cep290-mutant mice. Unexpectedly, blind CEP290-mutant human retinas retained photoreceptor and inner laminar architecture in the cone-rich central retina, independent of severity of visual loss. Surrounding the cone-rich island was photoreceptor loss and distorted retina, suggesting neural-glial remodeling. The mutant mouse retina at 4-6 weeks of age showed similar features of retinal remodeling, with altered neural and synaptic laminae and Muller glial activation. The visual brain pathways in CEP290-LCA were anatomically intact. Our findings of preserved foveal cones and visual brain anatomy in LCA with CEP290 mutations, despite severe blindness and rapid rod cell death, suggest an opportunity for visual restoration of central vision in this common form of inherited blindness.

Magnetic Resonance Imaging

Mutation

Antigens, Neoplasm - genetics

Visual Pathways

Blindness - physiopathology

Brain - physiopathology

Humans

Middle Aged

Macaca fascicularis

Male

Photoreceptor Cells, Vertebrate - physiology

Blindness - genetics

Animals

Mice, Mutant Strains

Adolescent

Adult

Female

Mice

Blindness - therapy

Neoplasm Proteins - genetics

Child

Details

Title: Subtitle: Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis
Creators: Artur V Cideciyan - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. cideciya@mail.med.upenn.edu
Tomas S Aleman
Samuel G Jacobson
Hemant Khanna
Alexander Sumaroka
Geoffrey K Aguirre - University of Pennsylvania
Sharon B Schwartz
Elizabeth A M Windsor
Shirley He - University of Michigan
Bo Chang
Edwin M Stone
Anand Swaroop
Resource Type: Journal article
Publication Details: Human mutation, Vol.28(11), pp.1074-1083
DOI: 10.1002/humu.20565
PMID: 17554762
NLM abbreviation: Hum Mutat
ISSN: 1059-7794
eISSN: 1098-1004
Publisher: United States
Language: English
Date published: 11/2007
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983980294302771

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